Organocatalytic Decarboxylation of Amino Acids as a Route to Bio-based Amines and Amides

Article abstract of DOI:10.1002/cctc.201900800

Amino acids obtained by fermentation or recovered from protein waste hydrolysates represent an excellent renewable resource for the production of bio-based chemicals. In an attempt to recycle both carbon and nitrogen, we report here on a chemocatalytic, metal-free approach for decarboxylation of amino acids, thereby providing a direct access to primary amines. In the presence of a carbonyl compound the amino acid is temporarily trapped into a Schiff base, from which the elimination of CO₂ may proceed more easily. After evaluating different types of aldehydes and ketones on their activity at low catalyst loadings (≤5 mol%), isophorone was identified as powerful organocatalyst under mild conditions. After optimisation many amino acids with a neutral side chain were converted in 28–99 % yield in 2-propanol at 150 °C. When the reaction is performed in DMF, the amine is susceptible to N-formylation. This consecutive reaction is catalysed by the acidity of the amino acid reactant itself. In this way, many amino acids were efficiently transformed to the corresponding formamides in a one-pot catalytic system.

Full text of DOI:10.1002/cctc.201900800

Accepted Article
Title: Organocatalytic decarboxylation of amino acids as a route to bio-
based amines and amides
Authors: Laurens Claes, Michiel Janssen, and Dirk De Vos
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Organocatalytic decarboxylation of amino acids as a route to bio-
based amines and amides
Laurens Claes, Michiel Janssen, and Dirk E. De Vos*[a]
Abstract: Amino acids obtained by fermentation or recovered from (≤ 5 mol%), isophorone was identified as powerful organocatalyst
protein waste hydrolysates represent an excellent renewable resource under mild conditions. After optimisation many amino acids with a
for the production of bio-based chemicals. In an attempt to recycle both neutral side chain were converted in 28-99% yield in 2-propanol at
carbon and nitrogen, we report here on a chemocatalytic, metal-free 150 °C. When the reaction is performed in DMF, the amine is
approach for decarboxylation of amino acids, thereby providing a direct susceptible to N-formylation. This consecutive reaction is catalysed by
access to primary amines. In the presence of a carbonyl compound the the acidity of the amino acid reactant itself. In this way, many amino
amino acid is temporarily trapped into a Schiff base, from which the acids were efficiently transformed to the corresponding formamides in
elimination of CO2 may proceed more easily. After evaluating different a one-pot catalytic system.
types of aldehydes and ketones on their activity at low catalyst loadings
Introduction
Moreover, the scope is limited to amino acids with aliphatic and
aromatic side chains, from which the corresponding primary amines
are isolated only in moderate yield (up to 68%). Wallentin and co-
workers developed a photocatalytic approach, which is more
promising in terms of scope, yield and conditions, but a protecting
group is required on both the amine moiety and side chain
functional groups to obtain high selectivity in the presence of radical
species.[18] Decarboxylation is also a step in several photoredox-
based carbon-carbon bond-forming reactions using protected
amino acids as a coupling partner.[19]-[23]
Transition metal-free approaches for amino acid
decarboxylation have been reported as well. For instance, the
formation of biogenic amines in food and beverages is related
either to the presence of carbohydrate- or lipid-derived reactive
carbonyl compounds,[24],[25] or to the action of amino acid
decarboxylases containing pyridoxal 5’-phosphate (PLP) or a
pyruvoyl group as cofactor.[26],[27] In these systems the
decarboxylation is facilitated by the formation of a Schiff base
adduct between the amino acid and the carbonyl compound, which
allows to stabilise charged intermediates by electron delocalisation
in a conjugated system (Scheme 1). Moreover, these enzymes are
able to tune the selectivity towards decarboxylation rather than to
transamination or racemisation by exploiting stereo-electronic
interactions between the Schiff base adduct and the surrounding
protein matrix.[28]-[31] The decarboxylation of amino acids has been
performed with isolated enzymes,[32]-[34] but the expensive PLP
cofactor is slowly consumed by transamination and the long-term
stability can also be an issue, even after immobilisation.[35]
Amino acids have nowadays major applications in human health
and nutrition as well as in animal feed formulation. Bulk production
processes based on fermentation and enzymatic catalysis have
been developed to meet the global demand, which nowadays
exceeds 5 million tons per year.[1],[2] Amino acids can also be
obtained by hydrolysis of protein-rich biomass residuals from the
agro-, food and biofuel industries, e.g. wheat dried distillers grains
with solubles, sugar beet/cane vinasses or slaughterhouse waste.[3]
However, protein waste has often poor nutritional quality and
should therefore rather be considered as a renewable resource of
both carbon and nitrogen for the chemical industry.[4]-[8]
Selective modification or elimination of the carboxylic acid
moiety at the -carbon of amino acids provides direct access to a
range of value-added nitrogenous chemicals.[9]-[14] We showed
earlier that the majority of the amino acids present in plant protein
hydrolysates can be converted into amino alcohols by Rh-catalysed
hydrogenation,[14] or into nitriles by electrochemical or transition
metal-catalysed oxidative decarboxylation.[11] In this work we study
the decarboxylation of amino acids to bio-based amines; the latter
have applications in the synthesis of polymers, pharmaceuticals
and agrochemicals.[15][16]
The non-oxidative decarboxylation of amino acids is
catalysed by homogeneous transition metal complexes, such as
CuI-phenanthroline.[17] However, this method involves high catalyst
loadings (10 mol%) and proceeds at high temperature (> 180 °C).
[a]
Dr. L. Claes, M. Janssen, Prof. dr. D. E. De Vos
Department of Microbial and Molecular Systems, Centre for
Membrane Separations, Adsorption, Catalysis, and Spectroscopy
for Sustainable Solutions
KU Leuven
Celestijnenlaan 200F box 2461, 3001 Leuven, Belgium
E-mail: dirk.devos@kuleuven.be
Supporting information for this article is given via a link at the end of
the document.
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In an attempt to mimic the enzymatic approach, both aliphatic (entry 5), aliphatic and aromatic aldehydes (entries 6-7), saturated
and aromatic carbonyl compounds have been proposed as suitable cyclic ketones (entry 11) and aromatic ketones (entries 12-13). On
mediators for amino acid decarboxylation. Although these the other hand, low but clear activities were observed for pyrrole-
compounds have often been evaluated as stoichiometric and indole-based aldehydes (entries 8-9) and aliphatic ketones
reagents,[36]-[50] they are not consumed according to the mechanism (entry 10); the yield of 2a was typically < 30%. Aryl aliphatic ketones
(Scheme 1). However, their ability to act as a catalyst has only with an electron-donating substituent at the o- or p-position of the
rarely been exploited before. Promising results were obtained for aromatic ring produce 2a in higher yields, even > 50% (entries 26-
,-unsaturated ketones like 2-cyclohexen-1-one in certain case 27 versus 25 and 28-29). However, acetophenone itself was
studies, but reactions were still applied with rather high catalyst partially consumed by transamination to 1-phenethylamine (entry
loadings and at high temperature.[41]-[50] Therefore, this study aims 25). ,-Unsaturated ketones (entries 14-24), in particular the
to identify
a
performant organocatalyst for amino acid derivatives of 2-cyclohexen-1-one (entries 18-21 and 23), are
decarboxylation, which is active at low loadings (≤ 5 mol%) and among the most active organocatalysts: for instance, 2a was
under relatively mild conditions (≤ 150 °C).
produced in > 85% yield within 4 h by using isophorone or 3-
phenyl-2-cyclohexen-1-one. These catalysts increased the amine
yield at least by a factor 10 compared to the thermal reaction. Also
carvone seems to perform very well even at a relatively low
temperature and at a low catalyst loading (entry 23). This terpenoid-
based ,-unsaturated ketone was recently applied by Morrison
and co-workers in the decarboxylation of 1a, though under more
drastic conditions: they performed the reaction at 190 °C with two
molar equivalents of carvone, and obtained 2a in 78% yield within
5 min.[48] Here we show that a similar yield can be obtained by using
isophorone under milder conditions and at much lower catalyst
loadings. The latter is advantageous regarding catalyst efficiency
and product purification.
The differences in reactivity between these carbonyl
compounds can be rationalised in terms of the mechanism
(Scheme 1). Performant organocatalysts, viz. aryl aliphatic ketones
and ,-unsaturated ketones, contain a molecular motif that
enables electron delocalisation in a conjugated system and
stabilises the azomethine ylide intermediate (IV) obtained by
decarboxylation of the Schiff base adduct (III). A higher reactivity
was observed for ketones that contain an electron-donating
substituent on the aromatic ring (Table 1, entries 26-27 versus 25
and 28-29). However, ketones that contain two aromatic moieties
were almost inactive (entries 12-13), probably because the extent
of resonance stabilisation became too pronounced. A similar trend
was observed for ,-unsaturated cyclic ketones bearing a methyl
or phenyl substituent at position C-3 (entries 17 versus 16; 19-21
versus 18). Although the catalytic activity clearly depends on
resonance stabilisation, the electron density on the -carbon atom
of the substrate should remain sufficiently high to facilitate the
protonation of intermediate IV. In addition, the sp2-hybridised
carbon atoms of both the carbon-nitrogen and carbon-carbon
double bonds in III should be coplanar, preferably in a six-
membered ring, to facilitate electron delocalisation.[29] For instance,
a threefold increase in the yield of 2a was achieved by using 3-
methyl-2-cyclohexen-1-one instead of 3-methyl-2-cyclopenten-1-
one (entries 19 versus 17), because the latter suffers from a higher
ring strain. The difference in activity between 1-tetralone and 1-
indanone can be explained in a similar manner (entries 30 versus
31). The high performance of isophorone can be attributed to the
presence of these key features in its molecular motif, and therefore
this ketone was selected for further investigation. Moreover,
isophorone is commercially available and cheap, as it is produced
by base-catalysed aldol condensation of acetone.
Scheme 1. Mechanism of the organocatalytic decarboxylation of -amino acids:
[A] condensation between the -amino acid (I) and the carbonyl compound (II);
[B] decarboxylation of the Schiff base adduct (III); [C] protonation of the
azomethine ylide intermediate (IV), and [D] hydrolysis of the Schiff base adduct
(V), with release of an amine (VI) and regeneration of the catalyst.
Transamination, where the carbonyl compound is consumed and the -amino
acid is converted to the corresponding aldehyde (VII), can be a competitive side
reaction.
Results and Discussion
Decarboxylation of amino acids to amines
Catalyst screening. The decarboxylation of phenylalanine (1a) to
2-phenethylamine (2a) was studied as a model reaction to assess
the intrinsic catalytic activity of different carbonyl compounds under
relatively mild conditions (Table 1; additional examples in the
Supporting Information (Table S1)). To that end, a catalyst loading
of 5 mol% was applied, which is low in comparison with previous
studies.[36]-[50] The thermal decarboxylation of 1a at 130 °C – in the
absence of any additional carbonyl compound – occurred only to a
limited extent (entry 1). First, structural analogues of PLP and the
pyruvoyl cofactor present in amino acid decarboxylases were
selected as potential organocatalysts, but pyridine-4-carbaldehyde,
4-acetylpyridine and methyl pyruvate showed no activity (entries 2-
4). These observations demonstrate clearly that the enzymatic
approach benefits from interactions between the Schiff base adduct
and the surrounding protein matrix in the active site. For instance,
the pyridine moiety in PLP can be protonated and is then able to
serve as a temporary electron sink which stabilises the azomethine
ylide intermediate (Scheme 1, IV).[29] The range of nearly inactive
carbonyl compounds further comprises dicarbonyl compounds
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Table 1. Decarboxylation of phenylalanine (1a) to 2-phenethylamine (2a): catalyst screening.[a]
Entry
Organocatalyst
Y2a [%][b]
Entry
Organocatalyst
Y2a [%][b]
1
–
6
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3-Methyl-2-cyclopenten-1-one
2-Cyclohexen-1-one
3-Methyl-2-cyclohexen-1-one
Isophorone
26
47
83
86
86
18
77
57
35
55
53
23
28
75
44
8
2
Pyridine-4-carbaldehyde
4-Acetylpyridine
Methyl pyruvate
6
3
5
4
6
5
2,4-Pentanedione
Butyraldehyde
13
13
9
3-Phenyl-2-cyclohexen-1-one
3-Methoxycarbonyl-2-cyclohexen-1-one
(R)-Carvone
6
7
Benzaldehyde
8
Pyrrole-2-carbaldehyde
Indole-3-carbaldehyde
Acetone
25
32
32
13
14
10
51
63
16
1-Acetyl-1-cyclohexene
Acetophenone
9
10
11
12
13
14
15
16
2’-Methoxyacetophenone
4’-Methoxyacetophenone
2’-Bromoacetophenone
4’-Bromoacetophenone
1-Tetralone
Cyclohexanone
Benzophenone
9-Fluorenone
4-Methylpent-3-en-2-one
2,6-Dimethyl-2,5-heptadien-4-one
2-Cyclopenten-1-one
1-Indanone
2-Indanone
[a] Conditions: 1a (0.25 mmol), organocatalyst (0.0125 mmol), DMSO (1 mL), 130 °C, 4 h. [b] The yield (Y) of 2a was determined by GC analysis using benzonitrile as
the internal standard.
Optimisation of reaction conditions. The influence of several methylpyrrolidone (NMP) (entries 11 versus 13-15).[51] Remarkably,
parameters such as catalyst loading, time and solvent was studied N-(2-phenethyl)formamide and N-(2-phenethyl)acetamide were
for the isophorone-catalysed decarboxylation of 1a (see also identified as the main products after 24 h in DMF or DMAc
Supporting Information, Figures S1-S2). When the progress of the respectively, suggesting that 2a is susceptible to a consecutive N-
reaction under standard conditions was monitored in function of acylation thereby using the solvent as acyl donor (vide infra). Low-
time, the yield of 2a reached an optimum between 1 h and 4 h, and boiling solvents are however more attractive in terms of
decreased upon prolonging the reaction time to 24 h (Figure 1). A sustainability and product purification (entries 1-8, 10).
similar trend was observed at reduced catalyst loadings, e.g. 2.5
and 1 mol% isophorone. Although both the initial rate and yield
decreased by using only 1 mol% of isophorone, 2a was still
produced in about 70% yield within 4 h. On the other hand, when
the reaction was performed under solvent-free conditions, 2a was
obtained in 80% yield after 4 h. Nevertheless, further experiments
were conducted using a catalyst loading of 5 mol% isophorone.
The decarboxylation 1a was also performed in other solvents
than DMSO (Table 2). The selection was limited to polar solvents,
both protic and aprotic, mainly for reasons of amino acid solubility
and stabilisation of charged intermediates. The reaction did not
proceed in water (entry 1) because Schiff base condensation,
which is an essential step in the catalytic cycle, is inhibited.
Moreover, isophorone has a limited solubility in water. Among the
high-boiling solvents, DMSO remains the most appropriate choice
and this solvent is also less harmful than for instance N,N-
dimethylformamide (DMF), N,N-dimethylacetamide (DMAc) and N-
Figure 1. Variation of the catalyst loading in the decarboxylation of phenylalanine
(1a) to 2-phenethylamine (2a). Conditions: 1a (0.25 mmol), isophorone, DMSO
(1 mL), 130 °C. The yield of 2a was determined by GC analysis using benzonitrile
as the internal standard. Legend: () no catalyst, () 1 mol%, () 2.5 mol%, and
() 5 mol% of isophorone.
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Table 2. Isophorone-catalysed decarboxylation of phenylalanine (1a) to 2-phenethylamine (2a): solvent screening.[a]
Y2a [%][b]
24 h
Entry
Solvent
Tbp [°C]
Conditions[a]
2 h
n.r.[c]
37
4 h
n.r.[c]
44
82
81
62
64
29
55
18
33
86
n.r.[c]
9
1
Water
100
65
A
A
A
A
A
A
A
A
B
A
B
B
B
B
B
B
n.r.[c]
53
2[d]
3[e]
4[e]
5
Methanol
Ethanol
78
53
89
1-Propanol
97
40
89
2-Propanol
82
37
88 (83)[f]
88
6[e]
7
1-Butanol
118
100
82
44
2-Butanol
11
87
8
tert-Butanol
16
88
9
Ethylene glycol
Acetonitrile
198
82
23
10
10
11
12
13
14
15
16
16
42
Dimethyl sulfoxide
Formamide
189
210
153
166
202
287
85
74
n.r.[c]
11
n.r.[c]
8
N,N-Dimethylformamide
N,N-Dimethylacetamide
N-Methylpyrrolidone
Sulfolane
76
74
70
38
42
72
63
19
67
[a] Conditions A: 1a (1.25 mmol), isophorone (0.0625 mmol), solvent (5 mL), 130 °C, stainless steel autoclave. Conditions B: 1a (0.25 mmol), isophorone
(0.0125 mmol), solvent (1 mL), 130 °C, glass reactor. [b] The yield (Y) of 2a was determined by GC analysis using benzonitrile as the internal standard. [c] n.r. = no
reaction. [d] Phenylalanine methyl ester was obtained in 15%, 20% and 26% yield after 2 h, 4 h and 24 h, respectively. [e] The yield of phenylalanine alkyl ester
was always < 5%. [f] Isolated yield of the hydrochloride salt between brackets.
Whereas the yield of 2a proceeds through an optimum in function
of time in most polar aprotic solvents, such behaviour was not
observed for most protic solvents. Moreover, 2a was obtained in
almost 90% yield after 24 h in C2-C4 alcohols (entries 3-8). A lower
rate was observed in secondary alcohols (entries 5 versus 4; 7
versus 6) and 1a was partially consumed by esterification when
the reaction was carried out in methanol (entry 2). This side
reaction should be avoided because the decarboxylation does not
proceed from an amino acid ester. Therefore, 2-propanol was
considered as the most suitable solvent for decarboxylation.[51]
By switching the solvent from DMSO to 2-propanol, longer
reaction times were required to obtain 2a in high yield at 130 °C
(entry 5). The reaction time could be strongly reduced by
increasing the temperature: 2a was produced in 90% yield within
1 h at 150 °C (Supporting Information, Figure S3), whereas more
than 4 h were required to obtain a similar result at 130 °C.
Moreover, the high performance of isophorone can be maintained
at catalyst loadings as low as 0.5 mol%: 2a was produced in 87%
yield within approximately 4.5 h, whereas the yield was nearly
40% in the absence of catalyst. The latter result is remarkably
high in comparison with the thermal reaction in DMSO and can be
explained by the presence of acetone in the reaction mixture,
which may originate from solvent dehydrogenation under aerobic
conditions. Nevertheless, the catalytic effect of isophorone was
clearly demonstrated at short reaction times and therefore 150 °C
was selected as the optimal temperature for amino acid
decarboxylation in 2-propanol.
Substrate scope. The isophorone-based system was evaluated
for other amino acids (Table 3). Intrinsic differences in reactivity
among various substrates were demonstrated by performing the
decarboxylation for 4 h and 24 h. Besides, the solubility of amino
acids in the reaction medium should also be considered. Glycine
(1b) and amino acids with an aliphatic side chain such as alanine
(1c), valine (1d), leucine (1e), isoleucine (1f) and norleucine (1g)
were converted to the corresponding primary amines 2b-2g in
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Table 3. Scope of the isophorone-catalysed decarboxylation of amino acids to amines.[a]
2b: Y = 35% * / 99%
2c: Y = 59% * / 99% (99%)
2d: Y = 96% / 98% (80%)
2e: Y = 98% / 98% (79%)
2f: Y = 98% / 98% (87%)
2g: Y = 99% / 99%
2l: Y = 44% / 45%
2h: Y = 2% * / 29%
2m: Y < 1% / < 1%
2i: Y = 89% / 91%
2j: Y = 53% * / 99% (88%)
2k: Y = 30% * / 99% (94%)
2n: Y = 90% * / 99% (91%)
2o: Y < 1% * / < 1% [b]
2p: Y < 1% / < 1% [c]
2q: Y < 1% * / < 1% * [d]
2r: Y = < 1% * / < 1% [e]
2s: Y = 7% * / 9% *
2t: Y = 8% * / 28% * [f]
2u: Y = 90% * / 99%
2v: Y < 1% * / < 1% *
2w: Y = 7% * / 37% *
2x: Y =99% / 99% (97%)
[a] Conditions: amino acid (1.25 mmol), isophorone (0.0625 mmol), 2-propanol (5 mL), 150 °C, 4 h or 24 h, stainless steel autoclave. The yield (Y) of the amine was
determined by GC analysis using benzonitrile as the internal standard; isolated yield of the hydrochloride salt obtained after 24 h between brackets. Reactions with
incomplete substrate conversion are marked by an asterisk (*). [b] The yield of isopropyl pyroglutamate (4o) was 12% and 75% after 4 h and 24 h, respectively. [c]
The combined yield of methyl and isopropyl pyroglutamate (4o) was 32% and 85% after 4 h and 24 h, respectively. [d] Isopropyl acrylate (4q) was obtained in 5%
yield after 24 h. [e] The yield of 2-pyrrolidone was 7% and 11% after 4 h and 24 h, respectively. Isopropyl pyroglutamate was obtained in 32% and 64% yield after
4 h and 24 h, respectively. [f] The yield of -amino--caprolactam (4t) was 10% and 7% after 4 h and 24 h, respectively.
excellent yield (> 98%) after 24 h. Moreover, the reactivity of the
substrate increases with the length of the alkyl side chain. These
observations confirm that a higher electron density on the -
carbon in the substrate is beneficial regarding the protonation of
the azomethine ylide intermediate IV (Scheme 1, step C). Proline
(1x), which contains a secondary amine, shows an exceptionally
high reactivity since pyrrolidine (2x) was produced in 99% yield
within 4 h. In this case the decarboxylation proceeds through an
iminium cation-type intermediate. Within the class of amino acids
with an aromatic side chain, the reactivity of tryptophan (1i) is
similar to that of 1a, because tryptamine (2i) was obtained in 89%
yield within 4 h. However, the decarboxylation of tyrosine (1h) and
histidine (1w) was limited because of their low solubility in 2-
propanol. Serine (1j) and threonine (1k) were converted
successfully to ethanolamine (2j) and 1-amino-2-propanol (2k)
respectively, but the -amino alcohol from homoserine (1l) was
obtained in rather poor yield, even after 24 h. Methionine (1n) was
efficiently converted with 90% yield within 4 h, showing that the
thioether moiety was tolerated. Cysteine (1m), which contains a
thiol group in the side chain, was degraded completely at 150 °C;
GC-MS analysis revealed diethyl disulfide as major by-product.
The decarboxylation of amino acids with acidic and basic groups
in the side chain was unsuccessful. Both glutamic acid (1o) and
glutamine (1r) were converted to isopropyl pyroglutamate rather
than to -aminobutyric acid (2o) or -aminobutyramide (2r), even
when the free carboxylic acid group at the -position of 1o was
protected by esterification (1p). The lactamisation of 1o, 1p and
1r and subsequent esterification to alkyl pyroglutamates (5)
proceeded fast in an alcohol solvent at 150 °C (Scheme 2, A).
Although pyroglutamic acid is not able to form a Schiff base
adduct with isophorone, it should not be considered as a waste
product because it can be converted to 2-pyrrolidone by Pd-
catalysed decarboxylation under more drastic conditions.[12]
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Tandem decarboxylation – N-acylation of amino acids to
amides
When the isophorone-catalysed decarboxylation of 1a was
performed in DMF, N-(2-phenethyl)formamide (3a) was obtained
in 84% yield after 24 h, whereas the yield of 2a was < 10% (Table
4, entry 2). A similar side reaction was observed in DMAc, but the
yield of N-(2-phenethyl)acetamide (4a) was only 45% after 24 h
(entry 3). In both cases, the amide was produced by a consecutive
N-acylation (Figure 2), which proceeds by a nucleophilic attack of
2a on the carbonyl group in DMF or DMAc. GC-MS analysis
confirmed that dimethylamine remains as a co-product in solution.
The extent of N-acylation is dependent on the accessibility and
the electrophilic character of the carbonyl group in the acyl donor,
and was therefore more pronounced in DMF than in DMAc. In
contrast to the reaction in DMSO, the overall yield of amino acid
decarboxylation in DMF, taking into account both the amine 2a
and the amide 3a, remains nearly constant at longer reaction
times (Figure 2). Because both the amino acid reactant and the
corresponding amine are able to form Schiff base adducts with
isophorone, in situ modification of nucleophilic amines to inert
amides provides a strategy to perform the decarboxylation with
higher efficiency under mild conditions.
Scheme 2. Side reactions observed during the isophorone-catalysed
decarboxylation of certain amino acids: [A] lactamisation and esterification of
glutamic acid (1o) to an alkyl pyroglutamate (5); [B] deamination and
esterification of -alanine (2q) to an alkyl acrylate (6), and [C] lactamisation of
lysine (1t) to -amino--caprolactam (7).
Further, aspartic acid (1q) and asparagine (1s) were almost
unreactive under these conditions, mainly for reasons of solubility.
Isopropyl acrylate (6) was identified as the main product from 1q
instead of the expected -alanine (2q), suggesting that a
deamination step is involved (Scheme 2, B). Additional
experiments showed that acrylate esters were not obtained by
decarboxylation of fumaric acid under identical conditions, and
therefore decarboxylation must precede deamination in the
production of acrylates from 1q. The reactivity of lysine (1t) was
affected by the presence of an additional amino group in the side
chain. Indeed, Schiff base condensation occurs to a much lesser
extent under basic conditions and the -amino group is in
competition with the -amino group for Schiff base condensation
with isophorone. Moreover, lactamisation of 1t to -amino--
caprolactam (7) was observed as a side reaction (Scheme 2, C).
Isophorone loadings > 100 mol% might be beneficial for the
production of 1,5-pentanediamine (2t) in higher yields.
Alternatively, a protecting group on the -amino group of lysine,
as in N--acetyllysine (1u), allows to obtain the corresponding
amine 2u in 90% yield even within short reaction times. The lack
of reactivity observed for arginine (1v) can be explained in a
similar manner. Finally, this procedure for organocatalytic
decarboxylation of amino acids can be applied on gram scale
without loss in yield, which has been demonstrated for
phenylalanine and leucine (Supporting Information).
Figure 2. Time course plot for the tandem decarboxylation – N-formylation of
phenylalanine (1a) to 2-phenethylamine (2a) and N-(2-phenethyl)formamide
(3a). Conditions: 1a (0.25 mmol), isophorone (0.0125 mmol), DMF (1 mL),
130 °C. The yield of 2a and 3a was determined by GC analysis using
benzonitrile as the internal standard. Legend: () yield of 2a, () yield of 3a,
and () overall yield.
Table 4. Isophorone-catalysed decarboxylation of phenylalanine (1a) in high-boiling solvents.[a]
Y2a [%][b]
Y3a or 4a [%][b]
S3a or 4a [%][b]
Entry
Solvent
4 h
86
9
24 h
74
8
4 h
< 1
81
24 h
< 1
4 h
–
24 h
–
1
2
3
Dimethyl sulfoxide
N,N-Dimethylformamide (R = -H)
N,N-Dimethylacetamide (R = -CH3)
84 (75)
45
91
14
91
52
74
42
12
[a] Conditions: 1a (0.25 mmol), isophorone (0.0125 mmol), solvent (1 mL), 130 °C. [b] The yield (Y) of 2-phenethylamine (2a) and N-(2-phenethyl)formamide (3a)
or N-(2-phenethyl)acetamide (4a) were determined by GC analysis using benzonitrile as the internal standard; isolated yield between brackets. The selectivity (S)
to 3a was expressed by the ratio Y3a / (Y2a + Y3a), and analogously for 4a.
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Formamides are important intermediates in the synthesis of
agrochemicals, pharmaceuticals and isocyanides. They are
prepared from primary and secondary amines by organocatalysis,
acid- or transition metal-mediated catalysis, thereby using CO,
methanol, paraformaldehyde, formic acid or esters thereof as a
precursor of the carbonyl group.[52] In an alternative manner, they
can be produced by N-formylation of amines in DMF, which is for
instance catalysed by CeO2.[53] However, high metal loadings
(40 mol%) and elevated temperatures (up to 180 °C) are
generally required to produce formamides in high yield. The
tandem decarboxylation – N-formylation of amino acids was
observed here for the first time and is proposed as an alternative
route towards functionalised formamides, because both reactions
can be performed under mild conditions in a one-pot catalytic
system, even in the absence of transition metals. This two-step
reaction will therefore be studied in more detail.
Figure 3. Tandem decarboxylation – N-formylation of phenylalanine (1a, )
versus N-formylation of 2-phenethylamine (2a, ) in DMF. Conditions: 1a or 2a
(0.25 mmol), isophorone (0.0125 mmol), DMF (1 mL), 130 °C. The yield of N-
(2-phenethyl)formamide (3a) was determined by GC analysis using benzonitrile
as the internal standard.
Substrate scope. The catalytic system that was optimised for the
tandem decarboxylation – N-formylation of 1a is also able to
convert other amino acids to the corresponding formamides
(Table 5). A catalyst loading of 5 mol% isophorone was applied
and reactions were performed at 130 °C for 24 h to account for
eventual differences in substrate reactivity, as was demonstrated
earlier in Table 3. Formamides 3c-3g were obtained in > 90%
yield from alanine (1c), valine (1d), leucine (1e), isoleucine (1f)
and norleucine (1g). The formamide 3x derived from proline (1x)
was also obtained in excellent yield. However, the
decarboxylation of tryptophan (1i) proceeded to a lesser extent
compared to the reaction in 2-propanol. Remarkably, whereas the
decarboxylation of tyrosine (1h) and histidine (1w) was
unsuccessful in 2-propanol, the tandem reaction in DMF
produced the corresponding formamides 3h and 3w in 74% and
82% yield respectively. A similar result was obtained for aspartic
acid (1q), although the effect was less pronounced. Reducing the
concentration of nucleophilic primary amines in the reaction
medium by N-formylation increases the tendency of unconverted
amino acids towards Schiff base condensation with isophorone.
N-Formylation thus allows to overcome the major bottleneck in
Schiff base-mediated amino acid decarboxylation. Substrates
with a functionalised side chain can be converted with a higher
overall yield by the tandem process. The formamides 3j-3l and 3n
derived from serine (1j), threonine (1k), homoserine (1l) and
methionine (1n) were produced in good to excellent yield;
however cysteine (1m) was again degraded completely under
these conditions. Glutamic acid (1o), its 5-methyl ester derivative
(1p) and glutamine (1r) were mainly converted to pyroglutamic
acid (Scheme 2, A), which was subsequently formylated at its
amide nitrogen to N-formylpyroglutamic acid. Finally, lysine (1t)
was converted to a much higher extent in DMF than in 2-propanol,
because the reactivity of the -amino group in the side chain was
also diminished by N-formylation in DMF; N,N’-(pentane-1,5-
diyl)diformamide (3t) was obtained in 69% yield. The
decarboxylation proceeds even faster when the -amino group is
already protected at the onset of the reaction, as in N--
acetyllysine (1u). Finally, asparagine (1s) and arginine (1v) were
unreactive under these conditions.
Optimisation of reaction conditions. The tandem
decarboxylation – N-formylation of 1a was again selected as the
model reaction to study the effect of parameters such as catalyst
loading and temperature. Isophorone is the actual catalyst for the
decarboxylation of 1a in DMF: the conversion was negligible in
the absence of isophorone, but even 1 mol% of the ketone was
sufficient to increase the overall yield of 2a and 3a to 88% within
24 h (Supporting Information, Figure S4). A further increase in
catalyst loading to 2.5 or 5 mol% was beneficial in terms of rate
and overall yield, and may compensate for eventual catalyst
degradation. Indeed, isophorone was partially consumed by
transamination and subsequent N-formylation to N-(3,5,5-
trimethyl-2-cyclohexen-1-yl)formamide; the extent of catalyst
degradation can be as high as 20%. Further optimisation was
therefore performed using 5 mol% of isophorone. Although the
tandem reaction proceeds at 100 °C, the rate can be increased at
higher temperatures: the overall yield of 2a and 3a was 93% after
4 h at 150 °C, whereas at least 24 h were required to obtain the
same result at 100 °C (Figure S5). Product degradation at higher
temperatures was however not observed in DMF. The optimal
temperature was selected at 130 °C, because high overall yields
were obtained within 8 h under mild conditions.
Acid-catalysed N-formylation of amines. When 1a and 2a were
treated in the presence of isophorone in DMF under identical
conditions, 3a was produced with higher rate and in higher yield
from 1a than from 2a, respectively in 84% and 59% yield after
24 h (Figure 3). These observations suggest that the N-
formylation of 2a in the tandem process is catalysed by the
substrate 1a itself. The carboxylic acid group has a key role, which
was confirmed by additional experiments. First, when the
decarboxylation of 1a in DMF was performed in the presence of a
strong, non-nucleophilic base like 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU), the yield of 3a was reduced from 81% to 43% after
4 h (Supporting Information, Table S2). However, in this case the
decarboxylation step might also be influenced by the altered acid-
base conditions. Secondly, acidic additives facilitate the N-
formylation of 2a in DMF: the yield of 3a was increased from 19%
to 86% within 4 h by the addition of only 5 mol% acetic acid to the
reaction medium (Table S3).
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Table 5. Scope of the tandem decarboxylation – N-formylation of amino acids to formamides.[a]
3c: Y = 99% (S > 99%)
2c: Y < 1%
3d: Y = 91% (S = 95%)
2d: Y = 5%
3e: Y = 93% (S = 96%)
2e: Y = 4%
3f: Y = 94% (S = 94%)
2f: Y = 6%
3g: Y = 96% (S = 96%)
2g: Y = 4%
3h: Y = 74% (S = 92%)
2h: Y = 7%
3i: Y = 35% (S = 78%)
2i: Y = 10%
3j: Y = 98% (S = 98%)
2j: Y = 2%
3k: Y = 98% (S = 98%)
2k: Y = 2%
3l: Y = 76% (S > 99%)
2l: Y < 1%
3m: Y < 1%
2m: Y < 1%
3n: Y = 96% (S = 96%)
2n: Y = 4%
3o: Y < 1% [c]
2o: Y < 1%
3p: Y < 1% [d]
2p: Y < 1%
3q: Y = 21% (S = 53%)
2q: Y = 19%
3r: Y < 1% [e]
2r: Y < 1%
3s: Y = 3%
2s: Y = 2%
3t: Y = 69% (S = 88%)
2t: Y < 1%
3u: Y = 88% (S = 90%)
2u: Y < 1%
3v: Y < 1%
2v: Y < 1%
3w: Y = 82% (S = 95%)
2w: Y = 4%
3x: Y = 97% (S = 97%)
2x: Y = 3%
[a] Conditions: amino acid (0.25 mmol), isophorone (0.0125 mmol), DMF (1 mL), 130 °C, 24 h. [b] The yields (Y) of the amine and the amide as well as the selectivity
(S) to the amide were determined by GC analysis using benzonitrile as the internal standard. [c] The yields of pyroglutamic acid and N-formylpyroglutamic acid were
19% and 21% respectively. [d] The combined yield of pyroglutamic acid and methyl pyroglutamate was 47%, and the yield of N-formylpyroglutamic acid was 21%.
[e] The yields of 2-pyrrolidone and N-formylpyroglutamic acid were respectively 21% and 75%.
are obtained in DMF because the amines are susceptible to a
consecutive acid-catalysed N-acylation. The chemocatalytic
Conclusions
approach is especially useful in the valorisation of the neutral
amino acid fraction, and therefore highly complementary to the
enzymatic decarboxylation of acidic and basic amino acids.
Although the mechanism relies on Schiff base formation between
the amino acid and the ketone, the catalytic cycle may be inhibited
by the accumulation of amines in the process medium at high
conversion, because the ketone can be trapped in a Schiff base
adduct with the product. In situ modification of amines, for
example by N-acylation, can be a useful approach to achieve a
higher overall yield in amino acid decarboxylation.
Organocatalysis provides a powerful tool to perform the non-
oxidative decarboxylation of amino acids under relatively mild
conditions and in the absence of transition metals. Detailed
insights have been gained in the remarkably high activity of ,-
unsaturated ketones and in particular isophorone at low catalyst
loadings. The organocatalytic system allows to produce several
bio-based nitrogenous chemicals by simply changing the solvent:
many amino acids can be converted with good to excellent yields
to the corresponding amines in 2-propanol, whereas formamides
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Experimental Section
Scott, S. C. M. Witte-van Dijk, J. P. M. Sanders, N. Biotechnol. 2016, 33,
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General procedure for decarboxylation of amino acids. A
10 mL stainless steel reactor was charged with amino acid
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– N-
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Other experimental procedures for the synthesis of 2-
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available in the Supporting Information. Data on compound
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Acknowledgements
L.C. acknowledges the Agency for Innovation by Science and
Technology (IWT) in Flanders for a doctoral fellowship (grant
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Entry for the Table of Contents
FULL PAPER
Dr. Laurens Claes, Michiel Janssen and
Prof. dr. Dirk E. De Vos*
Page No. – Page No.
Organocatalytic decarboxylation of
amino acids as a route to bio-based
amines and amides
A catalytic system based on isophorone is able to convert a broad range of amino
acids to the corresponding amines in the absence of transition metals under mild
conditions. The decarboxylation can be coupled with the N-formylation of amines by
performing the reaction in DMF, resulting in a one-pot process to obtain amino acid-
derived formamides. Both methods provide opportunities for recycling nitrogen from
protein-rich biomass waste.
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